Safety and pharmacokinetics of the orally available antiprionic compound PRI‐002: A single and multiple ascending dose phase I study

Abstract

Introduction PRI‐002 is an orally available anti–amyloid beta (Aβ) prionic compound developed for direct disassembly of toxic Aβ oligomers relevant to Alzheimer's disease. Methods Two placebo‐controlled clinical phase I trials with oral dosing of PRI‐002 were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg PRI‐002 or placebo) in 40 participants followed by a multiple ascending dose study with daily 160 mg PRI‐002 for 14 days or 320 mg for 28 days in 24 participants. The main objectives were safety, tolerability, and evaluation of pharmacokinetic (PK) parameters. Results PRI‐002 was safe and well tolerated after single and multiple oral administration up to the highest doses. PRI‐002 was absorbed rapidly and drug exposure increased proportional to dose. During repeated daily administration, the drug accumulated by a factor of about three. Steady‐state conditions were reached after 1 to 2 weeks. Conclusions The safety and PK results encourage further clinical development of PRI‐002.

In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer’s Disease

“…In the recent years, RD2 has been studied extensively [ 10 , 11 , 12 , 13 ]. The efficacy of this compound has been demonstrated in several studies in different mouse models, so RD2 is now in the process of proving its efficacy in humans in clinical trials [ 9 ]. Out of several drug optimization approaches, the linear tandem- d -peptide RD2D3 and its cyclic equivalent, cRD2D3, came forth [ 12 , 14 , 15 , 22 ].…”

“…In order to optimize the lead structure, with respect to increased stability, affinity to Aβ(1-42), blood–brain-barrier (BBB) penetration, and in vitro potency and in vivo efficacy, rational drug design approaches were conducted. The most promising compound so far, called RD2, is currently under development for the treatment of patients with AD [ 9 ]. The suggested mode of action was demonstrated by successful target engagement in vitro and in vivo [ 10 , 11 ].…”

A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

“…The compound RD2 preferentially binds amyloid beta (Aβ) monomers with nanomolar affinity and stabilises Aβ in its native conformation [ 30 ], which is a novel strategy to directly disassemble toxic Aβ oligomers into native monomers [ 31 ]. RD2 has recently successfully passed a phase I clinical trial in healthy subjects (Single Ascending Doses (SAD) EUDRA-CT: 2017-000396-93 and Multiple Ascending Doses (MAD) EUDRA-CT: 2018-002500-14) [ 32 ] after demonstrating its preclinical efficacy in several AD mouse models [ 33 , 34 , 35 , 36 ]. The head-to-tail tandem version of RD2, RD2RD2, was originally designed to obtain a bivalent version of RD2 with potentially higher avidity and affinity for polyvalent Aβ assemblies.…”

A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an Als Mouse Model

“…The compound RD2 binds preferentially amyloid beta (Aβ) monomers with nanomolar a nity and stabilizes Aβ in its native conformation [30], which is a novel strategy to directly disassemble toxic Aβ oligomers into native monomers [31]. RD2 has recently successfully passed a phase I clinical trial in healthy subjects (Single Ascending Doses (SAD) EUDRA-CT: 2017-000396-93 and Multiple Ascending Doses (MAD) EUDRA-CT: 2018-002500-14) [32] after demonstrating its preclinical e cacy in several AD mouse models [33][34][35][36]. The head-to-tail tandem version of RD2, RD2RD2, was designed to obtain a bivalent version of RD2 with potentially higher avidity and a nity for polyvalent Aβ assemblies.…”